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High-grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer, and it is often associated with ascites at presentation. The objective of this study was to evaluate the accuracy of cytopathology to identify immunophenotypic features of HGSC and BRCA1/2 mutations from ascites.The study included 45 patients with histologically confirmed primary HGSC and malignant ascites. Immunocytochemistry (ICC) staining for PAX8, WT1, P53, P16, and Ki-67 was performed on cytospins and cytoblocks prepared from ascites. Next-generation sequencing (NGS) was used to detect germline/somatic BRCA1/2 mutations in the ascites. Both ICC and NGS results were compared with immunohistochemistry (IHC) and NGS results from tissue blocks of primary tumor. Cronbach α and χICC/IHC results for PAX8, WT1, P53, and P16 showed good reliability between cytospins, cytoblocks, and tissue blocks (α 0.75), whereas poor reliability and significant differences were observed for Ki-67 between ascites and tissue blocks (α 0.26; p.001 [Kruskal-Wallis]). For germline BRCA1/2 mutations, 100% concordance was confirmed, but only 14% concordance was confirmed for somatic mutations.These results demonstrate that cytopathology is an accurate method for identifying immunophenotypic features of HGSC and detecting germline BRCA1/2 mutations from ascites. However, further investigation is required for assessing the proliferation activity of HGSC in ascites and for detecting somatic BRCA1/2 mutations.

Background: The early detection of ovarian cancer is presently not effective, and it is crucial to establish biomarkers for the early diagnosis of ovarian cancer to improve the survival of patients. Materials and methods: The aim of this study was to investigate the role of thymidine kinase 1 (TK1) in combination with CA 125 or HE4 to serve as a potential diagnostic biomarkers for ovarian cancer. In this study, a set of 198 serum samples consisting of 134 ovarian tumor patients and 64 healthy age-matched controls were analyzed. The TK1 protein levels in serum samples were determined using the AroCell TK 210 ELISA. Results: A combination of TK1 protein with CA 125 or HE4 showed better performance than either of them alone in the differentiation of early stage ovarian cancer from the healthy control group, but also a significantly better performance than the ROMA index. However, this was not observed using a TK1 activity test in combination with the other markers. Furthermore, the combination of TK1 protein and CA 125 or HE4 could differentiate early stage disease (stage I, II) more efficiently from advanced-stage (stage III, IV) disease (p < 0.0001). Conclusions: The combination of TK1 protein with CA 125 or HE4 increased the potential of detecting ovarian cancer at early stages. Nasl. z nasl. zaslona. Opis vira z dne 6. 3. 2023. Bibliografija: str. 17-18. Abstract.

Background: In most cases, ovarian cancer is diagnosed at an advanced stage. The aim of this study was to determine if Primary Debulking Surgery (PDS) for women with advanced epithelial ovarian cancer is an equivalent treatment approach to neoadjuvant chemotherapy (NACT). Methods: A retrospective analysis of 214 women with stage FIGO IIIC and IV ovarian cancer was performed at the Institute of Oncology Ljubljana, Slovenia. Women were divided into two groups based on their primary treatment. The first group was the NACT group (184 women) and the second the PDS group (30 women). The selection of the women for PDS or NACT was based on the expertise of the gynecological-oncological surgeon and the image exam results. We used the Kaplan-Meier method for calculating Overall Survival (OS) and Progression-Free Survival (PFS). The statistical analysis was performed with IBM SPSS. Results: The median OS was lower in the NACT group than in the PDS group, 25 months (95% CI 20.6-29.5) and 46 months (95% CI 32.9-62.1), respectively. The PFS in the NACT group was 8 months (95% CI 6.4-9.5) and 18 months (95% CI 12.5-23.4) in the PDS group. For women treated with PDS the 5-year survival rate was 36.7% and 20.1% in the NACT group. Conclusion: In this study, the best survival results were observed in women treated with PDS, followed by adjuvant chemotherapy. If a woman is not suitable for surgery, NACT doubles the chance of a complete gross resection. Despite higher rates of complete gross resection after NACT, women treated with PDS (complete gross resection or optimal surgery) had higher OS.

Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients. Nasl. z nasl. zaslona. Opis vira z dne 12. 3. 2022. Bibliografija na koncu prispevka. Abstract.

Background Osteopontin (sOPN) is a promising blood tumour marker for detecting epithelial ovarian cancer (EOC). However, other clinical uses of sOPN as a tumour marker in EOC are still lacking. Since sOPN concentrations in serum are not associated with those in ascites, we compared clinical value of sOPN concentrations in the two body fluids. Patients and methods The study included 31 women with advanced EOC and 34 women with benign gynaecological pathology. In the EOC group, serum for sOPN analysis was obtained preoperatively, after primary debulking surgery and after chemotherapy. In the control group, serum was obtained before and after surgery. Ascites and peritoneal fluid were obtained during surgery. sOPN concentrations were determined by flow cytometry bead-based assay. Results The sensitivity and specificity of sOPN in detecting EOC was 91.2% and 90.3% (cut-off = 47.4 ng/ml) in serum, and 96.8% and 100% (cut-off = 529.5 ng/ml) in ascites. Kaplan-Meier analysis showed a significant association between higher serum sOPN concentration and overall survival (p = 0.018) or progression free survival (p = 0.008). Higher ascites sOPN concentrations were associated with suboptimally debulked tumour and unresectable disease. Higher serum sOPN concentrations were associated with refractory disease or incomplete response to platinum-based chemotherapy. Conclusions The study showed that ascites sOPN level mirrors present disease and is superior to serum level for diagnostic purposes and surgical planning, although the end result of treatment is the response of the whole body in fighting the disease. The preoperative sOPN concentration in serum thus better reflects disease outcome.

The aim of the study was to analyze the overall survival (OS) and progression free survival (PFS) of patients with high grade and advanced stage epithelial ovarian cancer (EOC) with at least 60 months of follow-up treated in a single gynecologic oncology institute. We compared primary debulking surgery (PDS) versus neoadjuvant chemotherapy plus interval debulking surgery (NACT + IDS) stratifying data based on residual disease with the intent to identify the rationale for therapeutic option decision and the role of laparoscopic evaluation of resectability for that intention. Patients and methods. This is observational retrospective study on consecutive patients with diagnosis of high grade and International Federation of Gynecology and Obstetrics (FIGO) stage III/IV EOC referred to our center between January 2008 and May 2012. We selected only patients with a follow-up of at least 60 months. Primary endpoint was to compare PDS versus NACT + IDS in term of progression free survival (PFS) and overall survival (OS). Secondary endpoints were PFS and OS stratifying data according to residual disease after surgery in patients receiving PDS versus NACT + IDS. Finally, through Cox hazards models, we tested the prognostic value of different variables (patient age at diagnosis, residual disease after debulking, American Society of Anesthesiologists (ASA) stage, number of adjuvantchemotherapy cycles) for predicting OS. Results. A total number of 157 patients were included in data analysis. Comparing PDS arm (108 patients) and NACT + IDS arm (49 patients) we found no significant differences in term of OS (41.3 versus 34.5 months, respectively) and PFS (17.3 versus 18.3 months, respectively). According to residual disease we found no significant differences in term of OS between NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0 or residual disease = 1, as well as no significant differences in PFS were found comparing NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0; contrarily, median PFS resulted significantly lower in PDS patients receiving optimal debulking (residual disease = 1) in comparison to NACT + IDS patients receiving complete debulking (residual disease = 0). PDS arm was affected by a significant higher rate of severe post-operative complications (grade 3 and 4). Diagnostic laparoscopy before surgery was significantly associated with complete debulking. Conclusions. We confirm previous findings concerning the non-superiority of NACT + IDS compared to PDS for the treatment of EOC, even if NACT + IDS treatment was associated with significant lower rate of post-operative complications. On the other hand, selecting patients for NACT + IDS, based on laparoscopic evaluation of resectabilty prolongs the PFS and does not worse the OS compared to the patients not completely debulked with PDS. Na odločitev o vrsti zdravljenja bolnikov z napredovalim melanomom lahko pomembno vpliva status mutacij v genih za BRAF, NRAS IN c-KIT. Pogostost mutacij in njihove medsebojne povezave s histološkimi značilnostmi tumorskih tkiv na slovenski populaciji do sedaj še niso bili raziskani. Bolniki in metode. Analizo smo izvedli retrospektivno. Mutacije BRAF, NRAS in c-KIT smo določili na 230 patoloških vzorcih bolnikov, ki smo jih nameravali zdraviti s sistemsko terapijo zaradi metastatskega melanoma na Onkološkem Inštitutu Ljubljana med leti 2013 in 2016. Zbrali smo histološke značilnosti primarnih tumorjev in klinične podatke bolnikov ter jih testirali na medsebojno povezanost z mutacijskim statusom. Rezultati. Povprečna starost 230 bolnikov je bila 59 let (razpon 25%85). Moških je bilo 141 (61,3 %) in žensk 89 (38,7 %). Ugotovili smo 129 (56,1 %) mutacij BRAF, 31 (13,5 %) NRAS in 3 (1,3 %) c-KIT mutacij v tkivnih vzorcih. Med 129 bolniki z mutacijami BRAF je imelo 114 (88,4 %) bolnikov mutacijo V600E in 15 (11,6 %) mutacijo V600K. Bolniki z BRAF mutacijami so bili ob diagnozi mlajši (52 v primerjavi s 59 let, p < 0,05), bolniki z NRAS mutacijami starejši (61 v primerjavi s 55 leti, p < 0,05). Število mutacij c-KIT je bilo prenizko za smiselno testiranje na medsebojne povezanosti, je pa bil eden izmed treh melanomov s c-KIT mutacijo melanom sluznice. Zaključki. Rezultati analize so v skupini slovenskih bolnikov z metastatskim melanomom odkrili visok delež mutacij BRAF ter nizek delež mutacij NRAS in c-KIT v primerjavi s predhodno objavljenimi raziskavami v Evropi in Severni Ameriki. Eden od glavnih vzrokov so specifične značilnosti naše študijske populacije, ki niso bile enake kot značilnosti celotne populacije bolnikov z melanomom.

In the last ten years, clinical oncology has been revolutionized by the introduction of oncological immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs) that transformed the standard of care of several advanced solid malignancies. Using ICIs for advanced gynecological cancers has yielded good results, especially for endometrial cancer. In ovarian or cervical cancer, combining ICIs with other established agents has shown some promise. Concurrently with the clinical development of ICIs, biomarkers that predict responses to such therapy have been discovered and used in clinical trials. The translation of these biomarkers to clinical practice was somewhat hampered by lacking assay standardization and non-comprehensive reporting of biomarker status in trials often performed on a small number of gynecological cancer patients. We can expect increased use of ICIs combined with other agents in gynecological cancer in the near future. This will create a need for reliable response prediction tools, which we believe will be based on biomarker, clinical, and tumor characteristics. In this article, we review the basic biology of ICIs and response prediction biomarkers, as well as the latest clinical trials that focus on subgroup effectiveness based on biomarker status in gynecological cancer patients.

Background High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples. Methods Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared. Results Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples. Conclusion There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients. Trial registration The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038.

Background Primary treatment of patients with advanced epithelial ovarian cancer consists of chemotherapy either before (neoadjuvant chemotherapy, NACT) or after primary surgery (adjuvant chemotherapy). The goal of primary treatment is no residual disease after surgery (R0 resection) what is associated with an improvement in survival of patients. There is, however, no evidence of survival benefits in patients with R0 resections after prior NACT. Methods We retrospectively reviewed the records of patients who were treated with diagnosis of epithelial ovarian cancer at Institute of Oncology Ljubljana in the years 2005–2007. The differences in the rates of R0 resections, progression free survival (PFS), overall survival (OS) and in five-year and eight-year survival rates between patients treated with NACT and patients who had primary surgery were compared. Results Overall 160 patients had stage IIIC epithelial ovarian cancer. Eighty patients had NACT and eighty patients had primary surgery. Patients in NACT group had higher rates of R0 resection (42% vs. 20%; p = 0.011) than patients after primary surgery. PFS was 14.1 months in NACT group and 17.7 months after primary surgery (p = 0.213). OS was 24.8 months in NACT group and 31.6 months after primary surgery (p = 0.012). In patients with R0 resections five-year and eight-year survival rates were 20.6% and 17.6% in NACT group compared to 62.5% and 62.5% after primary surgery (p < 0.0001), respectively. Conclusions Despite higher rates of R0 resections achieved by NACT, survival of patients treated with NACT was inferior to survival of patients who underwent primary surgery. NACT should only be offered to patients with advanced epithelial cancer who are not candidates for primary surgery.

Background The aim of the study was to establish whether there are different clinical entities of primary pulmonary choriocarcinoma (PPC) that deserve different diagnostic approach and the most optimal treatment. Patients and methods A systematic review with PubMed search was conducted to identify studies that reported cases of PPC. The eligibility criteria were histological diagnosis of pulmonary choriocarcinoma and thorough examination of the reproductive organs to exclude potential primary choriocarcinoma in the gonads. Furthermore, to illustrate the review we additionally present a patient referred at our institution. Results 55 cases (17 men) were included in the review with a median age of 34 years. Women with the history of gestational event showed better survival outcome than women without the history of gestational event. Patients treated with combined modality treatment (surgery and chemotherapy) survived longer than the patients without combined modality treatment. Furthermore, multivariate analysis of prognostic factors showed that the combined modality treatment had independent prognostic significance. Size of the tumour showed significant prognostic influence in univariate and multivariate analysis. Conclusions PPC is an extreme rarity with variable clinical characteristics and outcome. It is important to capture and treat patients in the early stages of the disease. Women with the history of gestational event may show better survival, therefore genetic examination could help us to predict patient’s prognosis. Surgery followed by adjuvant chemotherapy appears to represent the best treatment for PPC.

Onkologija, leto XXII, št. 1, junij 2018, Onkologija, Volume XXII, No. 1, June 2018

Background. Contralateral breast cancer (CLB) is the most common second primary breast cancer in patients diagnosed with breast cancer. The majority of patients harbouring CLB tumours develop the invasive disease. Almost all invasive carcinomas are believed to begin as ductal carcinoma in situ (DCIS) lesions. The sensitivity of MRI for DCIS is much higher than that of mammography. Case report. We report the case of a woman who was treated with breast conserving therapy 10 years ago. At that time the invasive medullary carcinoma was diagnosed in the left breast. Ten years later mammographically occult DCIS was diagnosed with MRI-guided core biopsy in contralateral breast. Conclusions. There might be a potential role of MRI screening as part of an annual follow-up for patients diagnosed with breast cancer.

Background Phase II studies have shown that the combination of capecitabine and irinotecan (the XELIRI regimen) is active in metastatic colorectal cancer (MCRC). There are, however, no data about the use of the XELIRI regimen in the neoadjuvant treatment. Methods Patients with unresectable liver-only metastases of MCRC with ≤ 75 years of age were randomised to either the XELIRI (irinotecan 250 mg/m2 given on day one and capecitabine 1000 mg/m2 twice daily from day 2–15, every 21 days) or the FOLFIRI arm (irinotecan 180 mg/m2, 5-FU 400 mg/m2, LV 200 mg/m2, 5-FU 2400 mg/m2 (46-h infusion) – all given on day one, every 14 days). Primary end points were objective response rate (ORR) and rate of radical (R0) surgical resection. Secondary end points were progression-free survival (PFS), overall survival (OS) and safety. Results Altogether 87 patients were enrolled (41 pts in the XELIRI and 46 pts in the FOLFIRI arm). The median age was 63 years (63 years in the XELIRI and 62 years in the FOLFIRI arm) (p = 0.33). ORR was 49% in the XELIRI and 48% in the FOLFIRI arm (p = 0.76). The rate of radical R0 resection was 24% in both arms of patients. At the end of treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without evidence of the disease (CR+R0 resection) (p = 0.56). There were no statistical differences in grade 3 or 4 adverse events between both arms: diarrhoea 7% vs. 6%, neutropenia 5% vs. 13%, ischemic stroke 0 vs. 2%, acute coronary syndrome 2% vs. 4%, respectively. At the median follow up of 17 (range 1–39) months, the median PFS was 10.3 months in the XELIRI and 9.3 months in the FOLFIRI arm (p = 0.78), the median OS was 30.7 months in the XELIRI arm and 16.6 months in the FOLFIRI arm (p = 0.16). Conclusion The XELIRI regimen showed similar ORR as the FOLFIRI regimen in the neoadjuvant treatment of patients with MCRC. In addition, the XELIRI regimen showed similar PFS and OS with acceptable toxicity compared to the FOLFIRI regimen. Trial Registration Current Controlled Trials ISRCTN19912492